Chronic pain affects one in three Americans. Socioeconomic costs attributed to inadequate pain management are estimated at $100 billion per year. The classic demonstration that analgesia can be elicited by environmental stressors provides evidence for endogenous pain inhibitory systems. Stress-induced analgesia is mediated in part by endogenous opioids. However, stress analgesia that is insensitive to blockade with opioid antagonists provides evidence for endogenous nonopioid analgesic systems. The mechanism underlying nonopioid stress-induced analgesia is completely unknown. Narrowing this gap is critical to harness the potential of endogenous nonopioid mechanisms for suppressing pain. The objective of this application is to identify the mechanism underlying nonopioid stress-induced analgesia. The central hypothesis is that environmental stressors release endocannabinoids -endogenous ligands for cannabinoid receptors- that suppress sensitivity to pain. The proposed research is expected to demonstrate that nonopioid stress-induced analgesia is: 1) blocked by a cannabinoid antagonist, 2) suppressed in rats rendered tolerant to cannabinoids, 3) attenuated by cannabinoid CB 1 antisense receptor knockdown, and 4) mediated by endogenous cannabinoids. The applicant is well-positioned to undertake this work because her research demonstrates that cannabinoids suppress pain neurotransmission and provides preliminary data that validates the central hypothesis. Completion of these aims is critical for establishing the biological significance of an endogenous cannabinoid transmitter system for suppressing pain. The proposed work is significant because the potential of nonopioid mechanisms for suppressing intractable pain cannot be realized until the underlying endogenous analgesic systems have been identify led. Pharmacological interventions that manipulate levels of endogenous cannabinoids by increasing synthesis and/or inhibiting inactivation represent novel targets for drug development. The development of effective pharmacotherapies for pain is likely to have a profound impact by driving down escalating health care costs and improving the quality of human life.